The production of insulin is central to the regulation of carbohydrate and lipid metabolism. Insulin imbalances lead to conditions such as type II diabetes mellitus, a serious metabolic disease that afflicts around 5% of the population in Western Societies and over 150 million people worldwide. Insulin is secreted from pancreatic β cells in response to elevated plasma glucose which is augmented by the presence of fatty acids. The recent recognition of the function of the G-protein coupled receptor GPR40 in modulating insulin secretion has provided insight into regulation of carbohydrate and lipid metabolism in vertebrates, and further provided targets for the development of therapeutic agents for disorders such as obesity, diabetes, cardiovascular disease and dyslipidemia.
GPR40 is a member of the gene superfamily of G-protein coupled receptors (“GPCRs”). GPCRs are membrane proteins characterized as having seven putative transmembrane domains that respond to a variety of molecules by activating intra-cellular signaling pathways critical to a diversity of physiological functions. GPR40 was first identified as an orphan receptor (i.e., a receptor without a known ligand) from a human genomic DNA fragment. Sawzdargo et al. (1997) Biochem. Biophys. Res. Commun. 239: 543-547. GPR40 is highly expressed in pancreatic β cells and insulin-secreting cell lines. GPR40 activation is linked to modulation of the Gq family of intra-cellular signaling proteins and concomitant induction of elevated calcium levels. It has been recognized that fatty acids serve as ligands for GPR40, and that fatty acids regulate insulin secretion through GPR40. Itoh et al. (2003) Nature 422:173-176; Briscoe et al. (2003) J. Biol. Chem. 278: 11303-11311; Kotarsky et al. (2003) Biochem. Biophys. Res. Commun. 301: 406-410.
Various documents have disclosed compounds reportedly having activity with respect to GPR40. For example, WO 2004/041266 and EP 1559422 disclose compounds that purportedly act as GPR40 receptor function regulators. WO 2004/106276 and EP 1630152 are directed to condensed ring compounds that purportedly possess GPR40 receptor function modulating action. More recently, WO 2005/086661 U.S. Patent Publication No. 2006/0004012, US Patent Publication No. 2006/0270724, and US Patent Publication No. 2007/0066647 disclose compounds useful for modulating insulin levels in subjects and useful for treating type II diabetes.
Although a number of compounds have been disclosed that reportedly modulate GPR40 activity, the prevalence of type II diabetes, obesity, hypertension, cardiovascular disease and dyslipidemia underscores the need for new therapies to effectively treat or prevent these conditions.
Glucagon-like peptide 1 (GLP-1) is a peptide that is secreted from the enteroendocrine L-cells of the gut in response to an oral glucose load or food ingestion. The active forms of GLP-1 are processed from a precursor and are denoted GLP-1(7-37) and GLP-1(7-36) amide. GLP-1 has many effects on peripheral tissues. GLP-1 activates its cognate receptor GLP-1R (GLP-1 receptor) on pancreatic beta cells and potentiates glucose stimulated insulin secretion. Additionally, GLP-1 decreases glucagon levels, increases insulin biosynthesis, increases beta cell mass, decreases beta cell apoptosis and inhibits gastric emptying. These activities contribute to an improvement in hyperglycemia, and GLP-1 and GLP-1 mimetics have proven useful in the treatment of type 2 diabetes. GLP-1 has also been found to decrease body weight. Therefore, GLP-1 secretagogues may be useful in treating obesity and preparing medicaments for treating obesity. The decrease in body weight may result from the activities of GLP-1 to inhibit gastric emptying and to increase satiety. The GLP-1 receptor is also expressed in the heart and GLP-1 has been demonstrated to have cardioprotective effects and may be useful in the treatment of cardiovascular disease. The importance of GLP-1 with respect to diabetes, obesity and cardioprotection underscores a need for new therapies and compounds that stimulate GLP-1 secretion.